pg-545 has been researched along with Neoplasms* in 5 studies
2 review(s) available for pg-545 and Neoplasms
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Immunomodulatory Activities of the Heparan Sulfate Mimetic PG545.
Heparanase regulates multiple biological activities that enhance tumor growth and metastatic spread. Heparanase cleaves and degrades heparan sulfate (HS), a key structural component of the extracellular matrix that serves as a barrier to cell invasion and also as a reservoir for cytokines and growth factors critical for tumor growth and metastasis. For this reason, heparanase is an attractive target for the development of novel anti-cancer therapies. Pixatimod (PG545), a heparanase inhibitor, has shown promising results in the treatment of multiple tumor types. PG545 offers a diversity of mechanisms of action in tumor therapy that include angiogenic inhibition, inhibition of growth factor release, inhibition of tumor cell migration, tumor cell apoptosis, activation of ER stress response, dysregulation of autophagy, and NK cell activation. Further investigation into the role that heparanase and its inhibitors play in tumor therapy can lead to the development of effective tumor therapies. Topics: Glucuronidase; Heparitin Sulfate; Humans; Neoplasms; Saponins | 2020 |
Heparanase Inhibition by Pixatimod (PG545): Basic Aspects and Future Perspectives.
Pixatimod is an inhibitor of heparanase, a protein which promotes cancer via its regulation of the extracellular environment by enzymatic cleavage of heparan sulfate (HS) and non-enzymatic signaling. Through its inhibition of heparanase and other HS-binding signaling proteins, pixatimod blocks a number of pro-cancerous processes including cell proliferation, invasion, metastasis, angiogenesis and epithelial-mesenchymal transition. Several laboratories have found that these activities have translated into potent activity using a range of different mouse cancer models, including approximately 30 xenograft and 20 syngeneic models. Analyses of biological samples from these studies have confirmed the heparanase targeting of this agent in vivo and the broad spectrum of anti-cancer effects that heparanase blockade achieves. Pixatimod has been tested in combination with a number of approved anti-cancer drugs demonstrating its clinical potential, including with gemcitabine, paclitaxel, sorafenib, platinum agents and an anti-PD-1 antibody. Clinical testing has shown pixatimod to be well tolerated as a monotherapy, and it is currently being investigated in combination with the anti-PD-1 drug nivolumab in a pancreatic cancer phase I trial. Topics: Animals; Antineoplastic Agents; Glucuronidase; Humans; Neoplasms; Saponins | 2020 |
2 trial(s) available for pg-545 and Neoplasms
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A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours.
PG545 (pixatimod) is a novel immunomodulatory agent, which has been demonstrated to stimulate innate immune responses against tumours in preclinical cancer models.. This Phase I study investigated the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of PG545 monotherapy. Escalating doses of PG545 were administered to patients with advanced solid malignancies as a weekly 1-h intravenous infusion.. Twenty-three subjects were enrolled across four cohorts (25, 50, 100 and 150 mg). Three dose-limiting toxicities (DLTs)-hypertension (2), epistaxis (1)-occurred in the 150 mg cohort. No DLTs were noted in the 100 mg cohort, which was identified as the maximum-tolerated dose. No objective responses were reported. Best response was stable disease up to 24 weeks, with the disease control rate in evaluable subjects of 38%. Exposure was proportional up to 100 mg and mean half-life was 141 h. The pharmacodynamic data revealed increases in innate immune cell activation, plasma IFNγ, TNFα, IP-10 and MCP-1.. PG545 demonstrated a tolerable safety profile, proportional PK, evidence of immune cell stimulation and disease control in some subjects. Taken together, these data support the proposed mechanism of action, which represents a promising approach for use in combination with existing therapies. Topics: Adult; Aged; Angiogenesis Inhibitors; Cohort Studies; Disease Progression; Dose-Response Relationship, Drug; Female; Humans; Immunomodulation; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pilot Projects; Saponins | 2018 |
PG545 enhances anti-cancer activity of chemotherapy in ovarian models and increases surrogate biomarkers such as VEGF in preclinical and clinical plasma samples.
Despite the utility of antiangiogenic drugs in ovarian cancer, efficacy remains limited due to resistance linked to alternate angiogenic pathways and metastasis. Therefore, we investigated PG545, an anti-angiogenic and anti-metastatic agent which is currently in Phase I clinical trials, using preclinical models of ovarian cancer.. PG545's anti-cancer activity was investigated in vitro and in vivo as a single agent, and in combination with paclitaxel, cisplatin or carboplatin using various ovarian cancer cell lines and tumour models.. PG545, alone, or in combination with chemotherapeutics, inhibited proliferation of ovarian cancer cells, demonstrating synergy with paclitaxel in A2780 cells. PG545 inhibited growth factor-mediated cell migration and reduced HB-EGF-induced phosphorylation of ERK, AKT and EGFR in vitro and significantly reduced tumour burden which was enhanced when combined with paclitaxel in an A2780 model or carboplatin in a SKOV-3 model. Moreover, in the immunocompetent ID8 model, PG545 also significantly reduced ascites in vivo. In the A2780 maintenance model, PG545 initiated with, and following paclitaxel and cisplatin treatment, significantly improved overall survival. PG545 increased plasma VEGF levels (and other targets) in preclinical models and in a small cohort of advanced cancer patients which might represent a potential biomarker of response.. Our results support clinical testing of PG545, particularly in combination with paclitaxel, as a novel therapeutic strategy for ovarian cancer. Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cisplatin; Drug Synergism; Female; Humans; Mice; Mice, Inbred C57BL; Mice, SCID; Neoplasms; Ovarian Neoplasms; Paclitaxel; Saponins; Tumor Cells, Cultured; Up-Regulation; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays | 2015 |
1 other study(ies) available for pg-545 and Neoplasms
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PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models.
PG545 is a heparan sulfate (HS) mimetic that inhibits tumour angiogenesis by sequestering angiogenic growth factors in the extracellular matrix (ECM), thus limiting subsequent binding to receptors. Importantly, PG545 also inhibits heparanase, the only endoglycosidase which cleaves HS chains in the ECM. The aim of the study was to assess PG545 in various solid tumour and metastasis models.. The anti-angiogenic, anti-tumour and anti-metastatic properties of PG545 were assessed using in vivo angiogenesis, solid tumour and metastasis models. Pharmacokinetic (PK) data were also generated in tumour-bearing mice to gain an understanding of optimal dosing schedules and regimens.. PG545 was shown to inhibit angiogenesis in vivo and induce anti-tumour or anti-metastatic effects in murine models of breast, prostate, liver, lung, colon, head and neck cancers and melanoma. Enhanced anti-tumour activity was also noted when used in combination with sorafenib in a liver cancer model. PK data revealed that the half-life of PG545 was relatively long, with pharmacologically relevant concentrations of radiolabeled PG545 observed in liver tumours.. PG545 is a new anti-angiogenic clinical candidate for cancer therapy. The anti-metastatic property of PG545, likely due to the inhibition of heparanase, may prove to be a critical attribute as the compound enters phase I clinical trials. Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Line, Tumor; Glucuronidase; HT29 Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Mice, SCID; Neoplasm Metastasis; Neoplasms; Saponins; Treatment Outcome; Xenograft Model Antitumor Assays | 2011 |